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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
A Pharmacologic Approach Against Glioblastoma-A Synergistic Combination of a Quinoxaline-Based and a PI3K/mTOR Dual
Vitória Santório de São José1,2,3, Bruno Marques Vieira3,4, Camila Saggioro de Figueiredo5
1Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
Abstract:
Glioblastoma (GB) is the most common malignant primary CNS tumor with a fast-growing and invasive profile. As a result of the poor prognosis and limited therapy available, glioblastoma shows a high mortality rate. Given the scarcity of effective chemotherapy options, multiple studies have explored the potential of tyrosine kinase inhibitors. To mitigate resistance and improve potency and selectivity, we proposed the combination of a potent irreversible epidermal growth factor receptor inhibitor-LASSBio-1971-and a potent phosphatidylinositol-3-kinase/mammalian target of rapamycin dual inhibitor-Gedatolisib-through an in vitro phenotypic study using five human GB lines. Here, we aimed to establish the cytotoxic potency, selectivity, and effect on proliferation, apoptosis, migration, and the cell cycle. Our data showed the cytotoxic potency of Gedatolisib and LASSBio-1971 and improved selectivity in the GB cell lines. They highlighted the synergistic response from their combination and its impact on migration reduction, G0/G1 cell cycle arrest, GB cytotoxicity, and apoptosis-inducing effects for different GB cell lines. The drug combination studies in phenotypic in vitro models made it possible to suggest a new potential treatment for glioblastoma that justifies further safety in in vivo phases of preclinical trials with the combination.
Insights
This study combined two inhibitors, LASSBio-1971 and Gedatolisib, to treat glioblastoma (GB). The combination showed synergistic effects, reducing migration and inducing apoptosis, suggesting a new potential glioblastoma therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma (GB) is an aggressive brain tumor with limited treatment options and high mortality.
- Existing therapies, including chemotherapy, have shown limited efficacy.
- Tyrosine kinase inhibitors are being explored as potential glioblastoma treatments.
Purpose of the Study:
- To evaluate the combination of LASSBio-1971, an epidermal growth factor receptor inhibitor, and Gedatolisib, a PI3K/mTOR dual inhibitor, for glioblastoma treatment.
- To assess the cytotoxic potency, selectivity, and effects on proliferation, apoptosis, migration, and cell cycle of the drug combination.
- To investigate the synergistic effects of combining LASSBio-1971 and Gedatolisib in human glioblastoma cell lines.
Main Methods:
- In vitro phenotypic study using five human glioblastoma cell lines.
- Evaluation of cytotoxic potency and selectivity of individual drugs and their combination.
- Assessment of effects on cell proliferation, apoptosis, migration, and cell cycle progression.
Main Results:
- Both Gedatolisib and LASSBio-1971 demonstrated cytotoxic potency and improved selectivity in glioblastoma cell lines.
- The combination of Gedatolisib and LASSBio-1971 exhibited a synergistic response.
- The combination significantly reduced glioblastoma cell migration, induced G0/G1 cell cycle arrest, and promoted apoptosis.
Conclusions:
- The combination of LASSBio-1971 and Gedatolisib shows significant anti-cancer effects in vitro against glioblastoma.
- This drug combination represents a promising new therapeutic strategy for glioblastoma.
- Further in vivo preclinical studies are warranted to evaluate the safety and efficacy of this combination therapy.
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